The proposed research is focused on the origin and composition of drusen and the pathogenesis of AMD. Preliminary studies have identified specific drusen-associated molecules (DRAMs), many of which are circulating plasma proteins and known participants in the process of fibrinolysis, thrombosis, inflammation, and/or the immune response. The emphasis of the proposal is on determining how normal and abnormal plasma proteins or the autoimmune response may be involved in the formation of drusen. To this end, four specific aims are designed to determine: (1) whether molecular abnormalities in drusen-associated plasma proteins are associated with the incidence of drusen and AMD; (2) whether specific molecular isoforms and/or abnormal concentrations of plasma proteins are associated with the incidence of drusen and AMD; (3) the nature of the autoimmune response associated with drusen and AMD; and (4) the effects of DRAMs on in vitro cell cultures. This proposal is related to two others through their common attempt to define a relationship between drusen, choroidal abnormalities and AMD.